Esters of tetraiodoanthranilic acid



United States Patent 3,218,349 ESTERS 0F TETRAIODOANTHRANILIC ACID John Harold Chapman, Ruislip, William Graham, Greenford, and Ronald Major Evans, Ickenham, England, assignors to Glaxo Laboratories Limited, Greenford, England, a British company No Drawing. Filed Feb. 27, 1963, Ser. No. 261,517 Claims priority, application Great Britain, May 12, 1958, 15,197/58 6 Claims. (Cl. 260-471) The present invention is concerned with improvements in or relating to new compounds of use as bronchographic X-ray contrast agents and to processes for the manufacture thereof. This application is a continuation-in-part of application Serial No. 811,778, filed on May 8, 1959 and now abandoned.

X-ray contrast agents suitable for use in bronchography should be stable compounds which may be presented in a form in which they become distributed uniformly throughout the bronchial tree; they should be retained in the bronchial tree for a sufficiently long period to en able X-ray photographs to be taken without undue haste yet without giving rise to substantial irritation of the tissues of the bronchial tree, but should on the other hand not persist in the bronchial tree for more than a few days. In general the agent should persist in the bronchial tree for more than 1 hour but not for more than four days. In addition, such compounds should be opaque to X-rays and should also be substantially non-toxic in the doses necessary to achieve X-ray opacity.

In general Water-soluble compounds are not retained in the bronchial tree for a sufiicient length of time for radiographical purposes and suitable bronchographic contrast agents are thus desirably Water-insoluble; they may be administered alone, if oils, or in solution or suspension in a suitable non-irritant liquid medium. Compounds containing iodine are generally to some extent opaque to X-rays and the degree of opacity is usually correlated with the percentage of iodine in the compound.

In the Journal of the American Pharmaceutical Association, 1953, volume XLII (1953), pages 721-728, V. H. Wallingford describes a large number of X-ray contrast agents one of which is 2-amino-3,5-diiodobenzoic acid. There is no mention, however, of the possibility of using 2-amino-3,S-diiodobenzoic acid as a bronchographic X- ray contrast agent, and indeed, as can be seen from Table II on page 724 of the reference, the substance is the most toxic of all the compounds considered, being said to have an LD in rats (that is the dosage required to kill 50% of the rats of 180 mg./kg.

It is an object of the present invention to provide an X-ray contrast agent which is particularly useful as an X-ray contrast agent in bronchography.

We have now found that lower alkyl esters of tetraiodoanthranilic acid (which are new compounds) possess many of the favourable characteristics outlined above and are therefore suitable as bronchographic agents, giving good X-ray opacity coupled with reasonable but not unduly prolonged persistence with low irritant properties. In particular the new compounds have outstandingly low toxicities being many times less toxic than the known 2- amino-3,5-diiodobenzoic acid referred to above.

According to the present invention therefore we pro- 3,218,349 Patented Nov. 16, 1965 "ice vide, as new compounds, compounds of the general formula I- COOR I NH;

i 1) in which R represents an alkyl group containing from 1 to 6 carbon atoms.

Preferred compounds with a particularly favourable balance of the characteristics required of a bronchographic contrast agent are those in which R represents a methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl or amyl group. Especially desirable properties are possessed by compounds in which R is a methyl, ethyl, propyl or iso-propyl group and the compound ethyl tetraiodoanthran-ilate is an outstandingly useful compound which is eminently suitable for use as a bronchographic contrast agent.

The new compounds according to the invention can be formulated for administration in any convenient way. Preferred compositions are those containing the anthranilate in a sterile liquid medium which may be of an aqueous or oily nature. Thus for example the new compounds may be formulated in aqueous suspensions which preferably contain a suspending agent and/ or a dispersing agent. Suitable suspending agents are various colloids, for example, vegetable gums, e.g., gum tragacanth, pectin, sodium carboxymethyl cellulose etc. Preferably non-ionic wetting agents are used as dispersing agents.

Where oily media are employed, preferred vehicles are the parentally acceptable vegetable oils e.g. arachis oil and sesame oil. Various oily esters may also be used.

Preparations containing the new compounds are preferably sterile and in the case of aqueous preparations are preferably made isotonic with sodium chloride.

The new esters according to the invention may be prepared in any convenient way. We have found that the most convenient syntheses proceed by way of tetraiodoanthranilic acid itself.

The esterificat-ion of tetraiodoanthranilic acid, however, is found to be somewhat difiicult to achieve by some conventional methods, e.g., by reaction of the appropriate alcohol with the acid, since the carboxyl group appears considerably sterically hindered and moreover the strong acid catalysts, for example sulphuric acid, boron trifluoride etherate or acyl chlorides, which are usually necessary in such a reaction, tend to split iodine from the nucleus. Azeotropic distillation is also generally unsuccessful. This difficulty can be largely overcome by, for example, reacting the silver salt of tetraiodoanthranilic acid with the appropriate halide or by reacting the acid with a diazo-alkane.

A method which we have surprisingly found to be particularly convenient for the esterification of tetraiodoanthranilic acid, however, is the reaction of a salt of tetraiodoanthranilic acid, preferably an alkali metal salt, with a dialkyl sulphate, an alkyl hydrogen sulphate or a sulphonic acid alkyl ester in the presence of a solvent medium of high dielectric constant. That such a method would be capable of ester formation without also alkylating the o-amino group is surprising in view of the ease with which primary amino groups are usually alkylated by dialkyl sulphates, and indeed the reaction may be successfully effected only under special conditions, namely in the presence of a solvent medium of high dielectric constant.

According to a feature of the present invention, therefore, we provide a process for the preparation of the alkyl esters of tetraiodoanthranilic acid in which a salt of tetraiodoanthranilic acid is reacted in a solvent medium of high dielectric constant with a dialkyl sulphate, alkyl hydrogen sulphate or sulphonic acid alkyl ester (the alkyl group(s) containing from 1 to 6 carbon atoms). The high-dielectric constant solvent media most suitable for this reaction include, for example, dimethyl formamide and dimethylacetamide. Preferably, water should be absent from the reaction mixture. The most convenient salts to be reacted in the process are sodium and potassium tetraiodoanthranilate, while the preferred alkylating agents are methyl, ethyl, propyl and isopropyl p-toluene sulphonate and the corresponding dialkyl sulphates. The reaction medium is preferably maintained non-acidic by addition of a suitable acid binding agent. Such an agent should not, of course, be capable of alkylation by the sulphate or sulphonate so that, in general, alkali-metal hydroxides, carbonates, bicarbonates or acetates are the most suitable compounds for this purpose. It is not necessary for the acid-binding agent to dissolve completely in the medium, a suspension maintained by stirring being found to be effective. A particularly suitable agent is potassium carbonate.

. The reaction is advantageously carried out at between 10 and 100 C. Conveniently the reaction mixture is neither heated nor cooled, the reaction being initiated at room temperature.

Tetraiodoanthranilic acid may conveniently be prepared by reacting tetraiodophthalic anhydride with ammonia to give tetraiodophthalamic acid which may then, in acid form or as a salt, be converted by the Hoffmann reaction, using a hypochlorite or hypobromite, for example, sodium hypochlorite or sodium hypobromite, to tetraiodoanthranilic acid. This reaction is preferably carried out in aqueous solution, alkali being added in the final stages after removal of unreacted halogen.

We have found that the reaction with ammonia is rendered somewhat difficult by the considerable insolubility of tetraiodophthalic anhydride in most organic solvents but that this reaction proceeds satisfactorily in the presence of high-dielectric constant media; dimethylsulphoxide and dimethylformamide have proved to be especially suitable as reaction media.

In order that the invention may be well understood we give the following examples by way of illustration only. In the examples, the salt of tetra-iodoanthranilic acid is first prepared by one of the following methods:

(a) Preparation of tetraiodoanthranilic acid (sodium salt) using dimethylsulphoxide as s'lvent.Tetraiodophthalic anhydride (250 g.) dissolved in dimethylsulphoxide (500 ml.) was treated with concentrated ammonia-solution (81 ml.). The clear solution was allowed to stand at room temperature for minutes and then sodium hydroxide (15.0 g.), dissolved in the minimum amount of water, was added. After a further half-hour, ethanol (360 ml.) and chloroform (800 ml.) were added to precipitate the sodium tetraiodophthalamate which was collected, washed with ethanol, and dried overnight. The whole product was treated with freshly prepared sodium hypochlorite (2 equivs.) in 500 ml. water and stirred at room temperature for 75 min. Sodium metabisulphite was then added to destroy any excess chlorine, followed by sodium hydroxide (15.4 g.) and the temperature raised to 6070 C. for 75 min. The warm suspension was poured into hydrochloric acid and the solid collected, washed with water and then dissolved in boiling dilute sodium hydroxide solution. On cooling sodium tetraiodoanthranilate (242 g.) crystallised as yellow plates.

In a similar way, one can prepare potassium and ammonium tetraiodoanthranilates 'by reaction with the corresponding hydroxides.

(b) Preparation of tetraiodoanthranilic acid using dimethyl formamide as solvent-0.880 ammonia (9 ml.) was added to a solution of tetraiodophthalic anhydride (25 g.) in dimethyl formamide ml.). After standing for ten minutes the resulting suspension was poured into aqueous sulphuric acid (2 N; ml.) and crushed ice. The solid was removed by filtration, washed with water and added to aqueous solution of sodium hypochlorite (100 ml.) and aqueous sodium hydroxide (10 N; 4 ml.). The reactants were stirred at room temperature for 75 minutes and the excess chlorine then removed by addition of a few drops of aqueous sodium metabisulphite. The mixture was then heated to 60-65 for 90 minutes, acidified with aqueous hydrochloric acid (2 N; 200 ml.) and the crude tetraiodoanthranilic acid removed by filtration. The crude acid was dissolved in a boiling solution of sodium hydroxide (4 g.) in Water (350 ml.) On cooling sodium tetraiodoanthranilate separated as yellow plates (20.32 g., 80%).

To prepare the free acid the sodium salt was transferred to boiling water (2 litres), the solution acidified and the product, tetraiodoanthranilic acid collected and recrystallised from ethanol as yellow needles, M.P. 211 C. (dec.). The free acid could then be converted to further salts thereof.

Example 1 .--M ethyl tetraiodoanthranilate Anhydrous potassium carbonate (5 g.) was suspendedin a solution of the sodium salt of tetraiodoanthranilic acid (33.1 g.) in dimethylformamide (300 ml.) by stirring. Dirnethyl sulphate (6.3 g.:5.0 ml.) was added as a single charge and the stirring was continued overnight at room temperature. The reaction mixture was diluted by the slow addition of boiling water (-400 ml.) and the methyl ester crystallized out. The product was filtered off, washed with hot water (3 x 50 ml.), methyl alcohol (2 x 30 ml.) and dried at 75 C. (1st crop).

More solid precipitated when the mother liquors were cooled to 0 C., and it was isolated as before (Crop 11).

1st cr0p.Yield of methyl tetraiodoanthranilate 27.25 g. (83% of theory). M.P. 155-6 C.

Mixed melting point with product obtained by alkylating with diazomethane 1546 C. I.R. spectrogram corresponded with product obtained using diazomethane.

2nd cr0p.Yie1d 0.95 g. (3% of theory). M.P. 155- 7 C.

Example 2.-Ethyl tetraiodoanthranilate The sodium salt of tetraiodoanthranilic acid (4.42 g.) prepared by method (a) described above was reacted with diethyl sulphate (1.02 g.) in dimethylacetamide (40 ml.) and using potassium carbonate (2.0 g.) to keep alkaline conditions, as described for the methyl ester.

Yield of ethyl ester 2.7 g. (60.5% of theory). -7 C.

Mixed melting point with the product obtained by alkylating with diazoethane caused no depression.

Example 3.Methyl tetraiodoanthranilate Sodium tetraiodoanthranilate prepared by method (a) described above (3.32 g.) was dissolved in dimethylformamide (40-ml.) and dimethyl sulphate (0.475 ml.) added. The mixture was stirred at room temperature overnight and worked up as described above to give the methyl ester (2.99 g., 91.5% of theory), M.P. 155.5-157 C. By followign this procedure the n-propyl, iso-propyl and n-butyl esters of tetraiodoanthranilic acid can be prepared.

Example 4 v (a) Methyl tetrai0d0anthranilate.Sodium tetraiodoanthranilate prepared by method (a) described above (3.32 g.) was dissolved in dimethylformamide (40 ml.) and potassium carbonate (1.52g.) followed by methyl p-toulenesulphonate (0.93 g.) added with stirring. The stirring was continued overnight and working up gave the methyl ester (2.72 g. 83% of theory), M.P. 155.5- 156.5 C., undepressed by an authentic sample.

(b) Propyl tetraiodoanthranilate.-By following the procedure of Example 4(a) using propyl p-toulenesulphonate, propyl tetraiodoanthranilate was obtained; M.P. 88-90 C.

Example 5 .-T he use of diazoethane to prepare the ethyl ester Tetraiodoanthranilic acid (23.9 g.) in dimethyl formamide (200 ml.) was reacted with diazocthane (750 ml., 0.29% ethereal solution) at 0. The excess diazoethane was neutralised with acetic acid. The solution diluted with ether (1 litre) and washed successively with water, aqueous sodium bicarbonate and water. The ethereal solution was dried, the solvent removed by distillation and the crude residue recrystallised twice from ethyl alcohol to give ethyl tetraiodoanthranilate (11.4 g., 46%), M.P. 127128 C.

We further give the following examples, by way of illustration only, of formulations of the compounds according to the invention, for use in bronchography:

Example 6.-Aque0us preparation Percent Ethyl tetraiodoanthranilate 50 Nonex 52 0.075

Sodium citrate 1.0 Sodium chloride 0.6 Benzyl alcohol 1.0 Sodium carboxy methyl cellulose 1.31

Distilled water, to 100.0

Example 7.-Oily preparation Percent Ethyl tetraiodoanthranilate 60.0 Arachis oil, to 100.0

We claim: 1. Ethyl tetraiodoanthranilate. 2. A compound of the formula I c o o R I NH in which R is an alkyl group containing from 1 to 6 carbon atoms, which comprises reacting a salt of tetraiodoanthranilic acid in a solvent medium of high dielectric constant selected from the group consisting of dirnethylformamide and dimethylacetamide with an esterifying agent selected from the group consisting of a dialkylsulphate, an alkyl hydrogen sulphate and a sulphonic acid alkyl ester, the alkyl group(s) of said esterifying agent containing from 1 to 6 carbon atoms.

4. A process according to claim 3 in which the reaction is effected at a temperature in the range of from 10 to C.

5. The process of claim 3 in which said solvent medium is dimethylformamide.

6. The process of claim 3 in which said solvent medium is dimethylacetamide.

References Cited by the Examiner UNITED STATES PATENTS 2,611,786 9/ 1952 Wallingford 260-471 2,813,118 11/1957 Galler 260-519 3,014,033 12/1961 Jansen et a1. 260-471 3,026,351 3/ 1962 Weigert 260-471 FOREIGN PATENTS 517,3 82 1/ 1940 Great Britain. 276,619 10/ 1951 Switzerland.

OTHER REFERENCES Lesser et al., Ber. Deut. Chem., 46, 3937-3946 (1913). Wallingford, V. H., I. Am. Pharm. Assoc., volume XLII, pages 724-8 (December 1953). I

LORRAINE A. WEINBERGER, Primary Examiner.

DANIEL D. HORWITZ, Examiner. 

2. A COMPOUND OF THE FORMULA 